Inorganic arsenic (iAs) is a common drinking water contaminant and one of the suspected environmental diabetogens. A consensus exists that chronic exposures to high levels of iAs in drinking water increase risk of diabetes mellitus. However, uncertainties remain about causality of this association, effects of low-level iAs exposures, and the role of lifestyle factors such as diet in modulating the risk of diabetes associated with iAs exposure. Our preliminary data and results from other laboratories suggest that dietary intake of various nutrients, and specifically donors of methyl groups modulate iAs metabolism, and thus may affect the adverse outcomes of iAs exposure, including development of diabetes. The goal of this exploratory project is to characterize the associations between dietary intakes of the methyl group donors (folate, cobalamin, and choline), iAs metabolism, and risk of diabetes using data and samples (plasma and DNA) collected in a previously established cohort of Chihuahua residents (n = 1,165) exposed to a wide range of iAs concentrations in drinking water. The dietary intakes will be evaluated using data previously collected by food frequency questionnaire (FFQ) and nutrient biomarkers in plasma (to be measured in the proposed project). Polymorphisms of genes involved in one carbon (the methyl group) metabolism that are also known to affect iAs metabolism or toxicity will be analyzed using DNA isolated from blood. Nutrient biomarkers in plasma and FFQ data will be used to identify dietary methyl group donors that interact with iAs exposure or metabolism (characterized by previously determined urinary profiles of iAs metabolites) to affect the risk of diabetes. We will also determine if any of the examined genetic polymorphisms modify iAs metabolism and/or the risk of developing diabetes. This exploratory project will be the first to examine the role of diet, and specifically dietary methyl group donors in development of diabetes associated with iAs exposure. This research will identify dietary factors that may decrease risk of diabetes in populations exposed to iAs in drinking water, thus providing important clues for future intervention studies, and ultimately for prevention or treatment of this disease.